More particularly, the invention relates to the preparation of the pure enantiomer (S)-(−)-omeprazole (esomeprazole), with the chemical name 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, and of its pharmaceutically acceptable alkali metal salts.
Very specifically, the present invention relates to the resolution of the potassium salts of racemic omeprazole by preferential crystallization and in particular by the AS3PC (Auto-Seeded Programmed Polythermic Preferential Crystallization) method.
Racemic omeprazole is represented by the following general formula (I):

The invention relates both to the omeprazole of above formula (I) and to its tautomeric form, and likewise as regards its salts and enantiomers below.
The pure enantiomer (S)-omeprazole (esomeprazole) is represented by the following general formula (II):

This pure enantiomer is sold as a drug in the form of the (S)-omeprazole magnesium salt trihydrate under the Nexium® name, represented by the following general formula (III):

It may be remembered that the magnesium salt of the (S) enantiomer of omeprazole is the first proton pump inhibitor (PPI) developed and sold in the pure enantiomer form. Racemic omeprazole and esomeprazole are employed to treat gastric and/or duodenal ulcers. They can be used in the prevention and treatment of gastrointestinal disorders, gastro-oesophageal reflux, digestive tract hemorrhage and dyspepsia. Furthermore, (S)-omeprazole can be of use in the treatment of psoriasis and in the treatment of infections with the bacterium Helicobacter pylori and related pathologies.
Omeprazole and its enantiomers belong to the chemical class of the prazoles comprising a benzimidazole or imidazopyridine ring system. Mention may be made, among the many prazoles sold or in the course of clinical development, of: ilaprazole, lansoprazole, leminoprazole, pantoprazole and rabeprazole/pariprazole in their racemic and/or pure enantiomer form.
These prazoles, and more particularly their corresponding alkali metal or alkaline earth metal salts, are used as inhibitors of gastric acid secretion and as such in the treatments.
They are chiral sulphoxides, the sulphur atom of which, bonded on the one hand to an oxygen atom and on the other hand to heteroaromatic ring A and methylene-heteroaromatic ring B substituents which are different, constitutes the stereogenic centre.
They can be represented by the following general formula (IV):

The change from omeprazole (racemic compound) to esomeprazole (pure laevorotatory (−) enantiomer of (S) absolute configuration) constituted, for this class of PPI pharmaceutical compounds, the first chiral switching. It has been shown that this compound, in its racemic form and each of its enantiomers, can exhibit different pharmacological and pharmacokinetic properties.
Omeprazole (racemic compound) was described for the first time in Patent EP 0 005 129 and some of its alkali metal salts in Patents EP 124 495 and U.S. Pat. No. 4,738,974.
The alkali metal and alkaline earth metal salts and more particularly the magnesium salt of omeprazole and those of other PPI prazoles have been shown to be stable and, in some cases, non hygroscopic.
A large number of documents of the prior art describe the preparation of esomeprazole and its alkali metal and alkaline earth metal salts.
Generally, these documents describe conventional methods which can be categorized according to the methods involved:
Erlandsson P. et al. published the first resolution of racemic omeprazole, carried out by chiral phase chromatography, in J. Chromatogr., 1990, 532, 305-319.
Patent Applications DE 40 35 455 and WO 94/27988 describe the resolution of racemic omeprazole and similar prazoles of pyridinylmethylsulphinyl-1H-benzimidazole type by fractional crystallization of diastereomeric salts and/or reverse phase chromatographic separation of covalent diastereomeric ethers of the type of chiral N-acyloxymethyl bonded to the free nitrogen atom N of the benzimidazole ring, followed by basic hydrolysis.
Patent Application US 2006/0089386 describes the resolution of racemic omeprazole using (S)-camphor-sulphonyl chloride by formation of covalent diastereomers separated by fractional crystallization, followed by basic hydrolysis, to give (S)-omeprazole >99% ee.
Patent Application WO 96/01623 describes the formation of the magnesium salts of the (R)- and (S)-omeprazole enantiomers with an enantiomeric excess of 99% ee with the crystalline form I.
Patent Application WO 96/17077 describes a method for the stereoselective bioreduction of the sulphoxide (racemic omeprazole) to give the corresponding sulphide (thioether) using microorganisms, such as Escherichia coli, Proteus mirabilis or Proteus vulgaris, comprising the enzyme DMSO reductase, or using this purified enzyme. This enantioselective bioreduction leaves the omeprazole greatly enriched in (+) enantiomer with an enantiomeric excess of 99% ee. The (−) enantiomer is obtained with 70% ee.
Patent Application WO 96/17076 describes a method for the stereoselective biooxidation of the precursor sulphide (thioether) of omeprazole in the presence of microorganisms, such as Penicillium frequentans, Brevibacterium paraffinolyticum or Mycobacterium sp., to give the (S)-omeprazole enantiomer of 99% ee.
Patent Application WO 96/02535 describes the asymmetric synthesis involving asymmetric oxidation of the prochiral sulphide using the catalytic system Ti(O-isoPr)4/diethyl D-tartrate/H2O in the presence of cumene hydroperoxide, of tertiary amine organic base and of organic solvent, such as toluene, followed by in situ formation of corresponding sodium salts. This catalytic process makes it possible to obtain chiral sulphoxides, in particular the sodium salt of (S)-omeprazole, of 99% ee.
Patent Application WO 2006/040635 describes the enantioselective synthesis of pyridinylmethylsulphinyl-benzimidazoles by catalytic oxidation of the corresponding precursor prochiral sulphide derivatives using the came catalytic system, Ti(O-isoPr)4/diethyl D-tartrate/H2O, cumene hydroperoxide and tertiary amine organic base, without addition of organic solvent, to give the (S)-omeprazole enantiomer and its alkali metal and alkaline earth metal salts, in particular its magnesium salt.
Patent Application WO 03/089408 describes the asymmetric synthesis of (S)-omeprazole by catalytic enantioselective oxidation of the precursor prochiral sulphide using a monodentate chiral ligand of methyl ester of L-mandelic acid type in the presence of cumene hydroperoxide and of Ti(O-isoPr)4/H2O, and in situ preparation of the corresponding sodium salt of 99% ee.
Patent Application WO 98/28294 describes the preparation of solid (S)-omeprazole in an amorphous form, a crystalline form (denoted form A) or a partially crystalline form (denoted form B).
Patent Application WO 98/54171 describes the formation of the magnesium salts of the (S) and (R) enantiomers of omeprazole dihydrate in the crystalline forms A and B and of the trihydrate. This patent also describes the formation of the potassium salts of the (S) and (R) enantiomers of omeprazole.
Patent Application WO 00/44744 describes the formation of a novel potassium salt of (S)-omeprazole hydrate of form B.
Patent Application WO 2004/002982 describes the separation of racemic omeprazole into its pure enantiomers by formation of diastereomeric salts starting from the sodium salt of racemic omeprazole brought together with the coordinating agent diethyl D-tartrate/Ti(iso-Pr)4 in acetone and complexing using L-mandelic acid.
The selective crystallization of the diastereomer comprising the (S)-omeprazole, followed by basic hydrolysis, gives the (S)-omeprazole magnesium salt trihydrate of 99% ee. The corresponding dihydrate is formed by controlled drying.
Patent Application WO 2004/046134 describes the preparation of (S)-omeprazole magnesium salt trihydrate of crystalline form II starting from the amorphous form of the same salt.
Patent Application WO 97/02261 (EP 1 498 416) describes the enantiomeric increase of mixtures of (S)/(R) enantiomers of omeprazole by selective precipitation of the corresponding racemic compound in acetone or acetonitrile solvents The filtrate gives, after evaporation, (S)-omeprazole of 98-99% ee.
In J. Phys. IV, 2004, 113, 11-15, Coquerel G. presents the rationale supporting the formation of the anticonglomerate (corresponding to racemic omeprazole) and its crystallization using binary phase diagrams (see FIG. 5b of this publication).
Patent Application WO 2004/089935 describes the preparation of a novel crystalline form of (S)-omeprazole magnesium salt trihydrate, known as H1, and the access to (S)-omeprazole magnesium salt hemihydrate and (S)-omeprazole magnesium salt monohydrate, each characterized by X-ray powder diffraction diagrams.
Patent Application WO 2006/001753 describes the preparation of (S)-omeprazole and sodium salts obtained in crystalline forms identified as C, E and H starting from the corresponding precursor potassium salt treated in a basic medium.
Patent Application WO 2006/003163 describes the preparation of novel crystalline forms of (S)-omeprazole which is a solvate of methanol, characterized by X-ray powder diffraction diagrams.
Patent Application WO 2006/134605 describes the formation of amorphous (S)-omeprazole hydrate and its conversion to the anhydride by resuspension in an organic solvent and filtering.
Patent Application WO 2004/076440 describes the I and II forms of (S)-omeprazole and its hydrates.
Patent Application WO 2004/020436 describes amorphous hydrates of the magnesium salt of (S)-omeprazole and their preparation.
Patent Application WO 2007/031845 describes the preparation of (S)-omeprazole magnesium salt trihydrate in two novel polymorphous crystalline forms G1 and G2 and the preparation of a corresponding amorphous form.
Patent Application. WO 2007/049914 describes the formation of an (S)-omeprazole strontium salt tetrahydrate in a crystalline form A and an amorphous form.
Deng J. et al., in Tetrahedron: Asymmetry, 2000, 11, 1729-1732, describe the resolution of racemic omeprazole by formation of inclusion complexes using (S)-(−)-2,2′-dihydroxy-1-1′-binaphthyl (BINOL), followed by crystallization and by chromatographic separation, to give (S)-omeprazole of 99% ee.
Patent Application WO 2007/074099 describes the resolution of racemic omeprazole by formation of inclusion complexes using the chiral ligand (S)-1,1,2-triphenyl-1,2-ethanediol. The complex of (S)-omeprazole and 2 equivalents of chiral ligand formed yields crystalline (S)-omeprazole of 99% ee.
While some of these methods are used on the industrial scale, regulatory change, in particular with regard to the safety and quality of pharmaceutical products, and also the economic impact of decisions of official health bodies in the direction of better control of the cost of treatments are forcing the development and the optimization of novel methods for the preparation of the (S)-omeprazole enantiomer and its salts of pharmaceutical interest.
Mention may be made, among the existing methods described in the above patents, without implied limitation, of a body of disadvantages commonly encountered and which are directly related to the use of these methods, it being possible for several of these disadvantages to be found in one and the same method:                In the case of the catalytic asymmetric synthesis involving catalysts of Ti(O-isoPr)4, vanadium trioxide or tungsten acetylacetonate type, the presence of residual heavy metals.        The formation of the sulphone, corresponding to the complete oxidation of the sulphur atom, which can be obtained at up to 40% with respect to the (S)-omeprazole and which is difficult to separate by chromatography or recrystallization.        The need to undergo a stage of chromatographic separation and of enantiomeric purification by recrystallization when the asymmetric synthesis methods provide (S)-omeprazole with a chemical purity <90% and with an enantiomeric purity <95% ee.        The use of a chiral phase HPLC chromatographic separation/purification method for direct chromatographic methods without involving covalent diastereomers or salts.        In the case of insufficient structural purity (Coquerel G., The ‘structural purity’ of molecular solids—An elusive concept? Chem. Eng. Process, 2006, 45, 857-862), when the enantiomer obtained in its neutral form or in the form of an alkali metal or alkaline earth metal salt, in particular the magnesium salt, is a mixture of forms, of hydrates and/or of solvates of different stabilities.        The removal of residual microorganisms and enzymes in the case of bioconversions.        
A specific aim of the present invention is to present a method for the preparation of the pure enantiomer (S)-omeprazole which does not exhibit the disadvantages described above.
This aim is achieved by virtue of the application of the preferential crystallization method to racemic omeprazole in the salt form. Thus, the invention relates very particularly to the application to potassium salts of racemic omeprazole of the resolution by preferential crystallization of each of its enantiomers, making it possible to obtain the eutomer (S)-omeprazole in an enantiomerically and chemically pure form.
In particular, the AS3PC preferential crystallization method has formed the subject of an entirely original development which excludes the restrictive use of crystallization seeds. This method is described, for example, in the following patents and patent applications FR 2 710 337, WO 95/08522, EP 0 720 595 and U.S. Pat. No. 6,022,409 and in G. Coquerel, Preferential Crystallization in Topic in Current Chemistry, Novel Optical Resolution Technologies, Springer, Berlin-Heidelberg, edited by K. Sakai, N. Hirayama and R. Tamura, 2007, 269, 1-51. This method is denoted “AS3PC” for “Auto-Seeded Programmed Polythermic Preferential Crystallization”.
The preferential crystallization methods are based on the alternating crystallization of the two (R) and (S) enantiomers of the same racemic chemical entity crystallizing in the conglomerate form in a medium which can be a solvent or a mixture of solvents or a combination of constituents including the solvent or solvents, this being the case for a given temperature range ΔT. Within this temperature range, this racemic mixture, in thermodynamic equilibrium with its saturated solution, is composed of two types of crystals each comprising only molecules with the same absolute configuration. Each enantiomer may incorporate molecules of solvent (solvates) and/or of water (hydrates).